Interleukin-4 (IL4) is a cytokine produced by several cell types, including activated T cells, mast cells and basophils, which exhibits multiple functions in the immune system. See, e.g., Paul, W. E., Blood 77: 1859–70 (1991). IL4 is a B cell growth factor, enhances cell surface expression of high affinity IgE receptors on mast cells and low affinity IgE receptors (CD23) on B cells and mononuclear phagocytes, and promotes immunoglobulin isotype switching to IgE. See, e.g., Coffman, R. L., et al. Adv Immunol 54: 229–70 (1993); Conrad, et al. J Immunol 141:1091–7 (1988); Keegan, et al. J Immunol 142: 3868–74 (1989); Noelle, et al. Proc Natl Acad Sci USA 81:6149–53 (1984); Vercelli, et al. J Exp Med 167: 1406–16 (1988). The immunoregulatory role of IL4 in allergic diseases and activation of Th2 type responses has been well demonstrated in mice. See, e.g., Kopf, et al. Nature 362: 245–8 (1993); Lohoff, et al. Int Arch Allergy Immunol 115: 191–202 (1993). IL4 binds cell-surface, high-affinity receptors that are heterodimers, consisting of a specific α subunit and common γc subunit that is shared with IL2, IL7, IL9 and IL15. See, e.g., Idzerda, et al. J Exp Med 171: 861–73 (1990). IL4R is required for ligand binding at the receptor. See, e.g., Yin, et al., J Biol Chem 269: 26614–7 (1994). There is substantial evidence from genome-wide searches that IL4R is a good candidate gene for allergy and atopy in humans. See, e.g., CSGA, Nat Genet 15: 389–92 (1997); Ober, et al. Hum Mol Genet 7: 1393–8 (1998). Identification of polymorphisms of the functional domains of human IL4R is important due to the essential role of the IL4R complex in IL4 signalling pathway. See, e.g., Deichmann, et al, Biochem Biophys Res Commun 231: 696–7 (1997); Hershey, et al. N Engl J Med 337: 1720–5 1997). According to data deposited in dbSNP as of September 2002, the 9 non-synonomous coding region polymorphisms of human IL4R are, with only one exception, clustered within a 600 base pair segment of exon 12.
Soluble forms of the human IL4 receptor have been described for use as an antagonist of IL4 activity. See, e.g., U.S. Pat. Nos. 5,767,065 and 6,328,954. However, the art has not described the IL4 receptor of other animals.
Atopy and recurrent airway obstruction (RAO; previously referred to as COPD or heaves) are common diseases in the horse (Equus caballus). The immunologic basis of RAO has been firmly established (see, e.g., Beadle, et al. Equine Veterinary Journal 34: 389–394 (2002); Lavoie, et al. American Journal of Respiratory & Critical Care Medicine 164: 1410–1413 (2001); Marti, E. and Harwood, L. Pferdeheilkunde 18: 587 (2002)) and the disease etiology appears similar, but not identical, to asthma in humans. Similarly, allergic diseases occur in dogs and cats.
The present invention addresses this and other problems.